Batch to continuous organic salt crystallisation : model based design

Student thesis: Doctoral Thesis


Organic salt crystallisation is of great importance to the pharmaceutical industry as the majority of pharmaceutical products are sold as salts with salt formation being an essential step in drug development. In this research a solution speciation model was developed to predict pH and solution composition during salt crystallisation processes. This tool allows for the entire salt crystallisation design space to be explored in terms of process pathways in the concentration vs. pH phase diagram. This allows for greater process understanding to be obtained and for theoretical solid yields to be determined.The model compound used in this work is the polymorphic organic salt ethylenediammonium 3,5-dinitrobenzoate (EDNB) which is the 2:1 salt of 3,5-dinitrobenzoic acid (3,5-DNBA) with ethylenediamine. In this system one of the two EDNB polymorphs (monoclinic and triclinic) or the 3,5-DNBA starting material may crystallise. The solution speciation model was used to predict the crystallisation pathway for each solid form and to guide the development of semi-batch and fully continuous crystallisation processes. In addition, aqueous pH-solubility measurements of EDNB triclinic and 3,5-DNBA were made to better understand EDNB salt solubility in high ionic strength solutions and to establish the operating space where 3,5-DNBA crystallisation is avoided.In this study EDNB crystallisation was experimentally performed in semi-batch and fully continuous processes. The semi-batch experiments demonstrated the scale up of the EDNB crystallisation process to 400 ml compared to 50 ml in literature. The fully continuous processes demonstrated that continuous mixing approaches could be used to crystallise the EDNB salt with consistent yield and PSD. Control over which polymorphic form crystallised was successfully demonstrated in both semi-batch and continuous mixing processes.
Date of Award6 Oct 2017
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsEPSRC (Engineering and Physical Sciences Research Council)
SupervisorJan Sefcik (Supervisor) & Alastair Florence (Supervisor)

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